Effect of Intravenous (IV) Vedolizumab on Mucosal Healing in Crohn's Disease

Conditions

Crohn's Disease

Keywords

Drug therapy

Brief summary

The purpose of this study is to evaluate endoscopic remission at Week 26 as assessed by ileocolonoscopy.

Detailed description

The drug being tested in this study is called vedolizumab. Vedolizumab is being tested to treat people who have Crohn's disease. This study will look at mucosal healing in people who take vedolizumab. The study will enroll approximately 100 patients and will be conducted in 2 Parts. Part A will consist of a 26-week treatment period and all participants will receive vedolizumab 300 mg intravenously (IV) on Day 1 and at Weeks 2, 6, 14 and 22. Part B will consist of a 26-week extension treatment period and all participants will receive vedolizumab 300 mg IV at Weeks 30, 38, and 46. This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 70 weeks for Parts A, B and 18-Week Follow-up combined. Participants will make multiple visits to the clinic. All participants included in the study will also have a 6 month safety follow-up telephone call following his/her last dose of study drug.

Jordi Rimola, Jean–Frédéric Colombel, Brian Bressler, Shashi Adsul, Jenifer Siegelman et al. (8 authors)

Clinical and Experimental Gastroenterology2024-01-0110 citations

10.2147/ceg.s429039

Vedolizumab treatment persistence and safety in a 2‐year data analysis of an extended access programme

Silvio Danese, Kavitha Subramaniam, Jan Van Zyl, Shashi Adsul, Dirk Lindner et al. (7 authors)

Alimentary Pharmacology & Therapeutics2020-11-1818 citations

10.1111/apt.16160

DOP15 Transmural healing with vedolizumab in patients with active Crohn’s disease

Jordi Rimola, J F Colombel, Brian Bressler, Shashi Adsul, Jenifer Siegelman et al. (8 authors)

Journal of Crohn s and Colitis2020-01-01

10.1093/ecco-jcc/jjz203.054

Endoscopic, Radiologic, and Histologic Healing With Vedolizumab in Patients With Active Crohn's Disease.

Danese S, Sandborn WJ, Colombel JF, Vermeire S, Glover SC, Rimola J, Siegelman J, Jones S, Bornstein JD, Feagan BG.

2019-07-04156 citations

10.1053/j.gastro.2019.06.038

Interventions

DRUGVedolizumab

Vedolizumab intravenous injection

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

No

Inclusion criteria

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. 2. Signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. 3. Has a diagnosis of moderately to severely active Crohn's disease (CD) at least 3 months prior to enrollment, with a Crohn's Disease Activity Index (CDAI) score of 220-450 during the Screening Period, a simple endoscopic score for Crohn's Disease (SES-CD) score of ≥7 and presence of at least one mucosal ulceration documented by recorded ileocolonoscopy at Screening assessed by the central reader. 4. Has CD with involvement of the ileum and/or colon that can be assessed by ileocolonoscopy. 5. Is male or female and aged 18 to 80 years, inclusive. 6. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 18 weeks after last dose. 7. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study and for 18 weeks after last dose. 8. Has demonstrated an inadequate response to, loss of response to, or intolerance of at least 1 of the following agents as defined below: * Immunomodulators: i. Has signs and symptoms of persistently active disease despite a history of at least one 12-week regimen of oral azathioprine (≥1.5 mg/kg) or 6-mercaptopurine (≥0.75 mg/kg), OR ii. Has a history of intolerance (including but not limited to nausea/vomiting, abdominal pain, pancreatitis, liver function test abnormalities, lymphopenia, thiopurine S-methyltransferase non wild type \[where wild type is defined as thiopurine S-methyltransferase (TPMT)\*1/\*1\], infection) to at least 1 immunomodulator. * Tumor necrosis factor- alpha (TNF-α) antagonists: i. Has signs and symptoms of persistently active disease despite a history of at least 1 induction with: 1. Infliximab: 4-week regimen of 5 mg/kg, 2 doses at 2 weeks apart, OR 2. Adalimumab: 2-week regimen of 160 mg on Day 1 and 80 mg on Day 15, OR 3. Certolizumab: 4-week regimen of 400 mg initially at Weeks 0, 2, 4 OR ii. Has recurrence of symptoms during maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify), OR iii. Has a history of intolerance of infliximab, adalimumab, or certolizumab, including but not limited to, infusion-related reaction, demyelination, congestive heart failure, or infection. * Corticosteroids i. Signs and symptoms of persistently active disease despite a history of at least one 4-week induction regimen that included a dose equivalent to prednisone 30 mg daily orally for 2 weeks or intravenous(ly) (IV) for 1 week, OR ii. Signs and symptoms of persistently active disease despite treatment with budesonide 9 mg daily or 6 mg daily for maintenance, OR iii. At least one failed attempt to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally, OR iv. History of intolerance to corticosteroids (including, but not limited to, Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, and infection). 9. May be receiving a stable therapeutic dose of conventional therapies for CD (excluding other biologic agents 60 days before enrollment). 10. Has a family history of colorectal cancer, personal history of increased colorectal cancer risk, age \>50 years, or other known risk factors must be up-to-date on colorectal cancer surveillance (may be performed during Screening).

Exclusion criteria

1. Has received a diagnosis of ulcerative colitis or indeterminate colitis. 2. Has clinical evidence of abdominal abscess. 3. Has a history of \>3 small bowel resections or diagnosis of short bowel syndrome. 4. Has extensive colonic resection, ie, subtotal or total colectomy with \<15 cm colon remaining. 5. Has ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine. 6. Has a history or evidence of adenomatous colonic polyps that have not been removed. 7. Has a history or evidence of colonic mucosal dysplasia. 8. Has intolerance or contraindication to undergo ileocolonoscopy. 9. Has active or latent tuberculosis, regardless of treatment history, as evidenced by any of the following: a. History of tuberculosis (TB). b. A diagnostic TB test performed during screening that is positive, as defined by: i. A positive QuantiFERON® test or 2 successive indeterminate QuantiFERON tests OR ii. A tuberculin skin test reaction ≥10 mm (≥5 mm in participants receiving the equivalent of \>15 mg/day prednisone). 10. Has chronic hepatitis B (HBV) or hepatitis C (HCV) infection. 11. Has any identified congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus \[HIV\] infection, organ transplantation). 12. Has evidence of active C. difficile infection or is having treatment for C. difficile infection or other intestinal pathogens during Screening. 13. Has evidence of an active infection during Screening. 14. Currently requires or has a planned surgical intervention for CD during the study. 15. Has received any investigational compound within 60 days of enrollment. 16. Has received any biologics within 60 days of enrollment. 17. Has received any live vaccinations within 30 days prior to enrollment. 18. Has conditions which, in the opinion of the investigator, may interfere with the participant's ability to comply with the study procedures. 19. Has any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal (GI), genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the investigator, would confound the study results or compromise participant safety. 20. Has a history of hypersensitivity or allergies to vedolizumab or its components. 21. Has had prior exposure to vedolizumab, natalizumab, efalizumab, or rituximab. 22. Had a surgical procedure requiring general anesthesia within 30 days prior to screening or is planning to undergo major surgery during the study period. 23. Has a history of malignancy, except for the following: adequately-treated nonmetastatic basal cell skin cancer; squamous cell skin cancer that has been adequately treated and that has not recurred for at least 1 year prior to Screening; and history of cervical carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years prior to screening. Participants with a remote history of malignancy (eg, \>10 years since completion of curative therapy without recurrence) will be considered based on the nature of the malignancy and the therapy received and must be discussed with the sponsor on a case-by-case basis prior to enrollment. 24. Has a history of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease. 25. Has a positive progressive multifocal leukoencephalopathy (PML) subjective symptom checklist during Screening or prior to the administration of study drug. 26. Has any of the following laboratory abnormalities during the Screening Period: i. Hemoglobin level \<8 g/dL. ii. White blood cell (WBC) count \<3\*10\^9/L. iii. Lymphocyte count \<0.5\*10\^9/L. iv. Platelet count \<100\*10\^9/L or \>1200\*10\^9/L. v. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3\*the upper limit of normal (ULN). vi. Alkaline phosphatase \>3\*ULN. vii. Serum creatinine \>2\*ULN. 27. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to enrollment. 28. Has an active psychiatric problem that, in the investigator's opinion, may interfere with compliance with study procedures. 29. Is unable to attend all the study visits or comply with study procedures. 30. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 18 weeks after participating in this study; or intending to donate ova during such time period. 31. If male, the participant intends to donate sperm during the course of this study or for 18 weeks thereafter. 32. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress. 33. Participants who are at sites participating in the magnetic resonance enterography (MREn) substudy may not participate if they have intolerance or contraindication to the procedure or if any of the following exclusions apply: 1. Has certain implanted medical devices, such as pacemakers or implantable cardioverter defibrillators (ICDs), or ferromagnetic metallic foreign bodies, such as shrapnel or certain tattoos. 2. Has allergy to gadolinium-based magnetic resonance (MR) IV contrast agents. 3. Has known claustrophobia. 4. Has estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73 m\^2 at Screening.

Design outcomes

Primary

Measure	Time frame	Description
Part A: Percentage of Participants Achieving Endoscopic Remission at Week 26	Week 26	Endoscopic remission is defined as a simple endoscopic score for Crohn's Disease (SES-CD) score of ≤4. The SES-CD evaluates 4 endoscopic variables (ulcer size, proportion of the surface area that is ulcerated, proportion of the surface area affected, and stenosis in 5 segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable is the sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.

Secondary

Measure	Time frame	Description
Part B: Percentage of Participants Achieving Complete Mucosal Healing at Week 52	Week 52	Complete mucosal healing is defined as absence of ulceration.
Part A: Percentage of Participants Achieving Endoscopic Remission at Week 14	Week 14	Endoscopic remission is defined as a SES-CD score of ≤4. The SES-CD evaluates 4 endoscopic variables (ulcer size, proportion of the surface area that is ulcerated, proportion of the surface area affected, and stenosis in 5 segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable is the sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.
Part B: Percentage of Participants Achieving Endoscopic Remission at Week 52	Week 52	Endoscopic remission is defined as a SES-CD score of ≤4. The SES-CD evaluates 4 endoscopic variables (ulcer size, proportion of the surface area that is ulcerated, proportion of the surface area affected, and stenosis in 5 segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable is the sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.
Part A: Percentage of Participants With Endoscopic Response at Week 14	Baseline and Week 14	Endoscopic response is defined as a reduction in SES-CD from Baseline by ≥50%. The SES-CD evaluates 4 endoscopic variables (ulcer size, proportion of the surface area that is ulcerated, proportion of the surface area affected, and stenosis in 5 segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable is the sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.
Part A: Percentage of Participants With Endoscopic Response at Week 26	Baseline and Week 26	Endoscopic response is defined as a reduction in SES-CD from Baseline by ≥50%. The SES-CD evaluates 4 endoscopic variables (ulcer size, proportion of the surface area that is ulcerated, proportion of the surface area affected, and stenosis in 5 segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable is the sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.
Part B: Percentage of Participants With Endoscopic Response at Week 52	Baseline and Week 52	Endoscopic response is defined as a reduction in SES-CD from Baseline by ≥50%. The SES-CD evaluates 4 endoscopic variables (ulcer size, proportion of the surface area that is ulcerated, proportion of the surface area affected, and stenosis in 5 segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable is the sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.
Part A: Percentage of Participants Achieving Complete Mucosal Healing at Week 26	Week 26	Complete mucosal healing is defined as absence of ulceration.
Part A: Percentage of Participants Achieving Clinical Response at Week 26	Baseline and Week 26	Clinical response is defined as CDAI decrease from Baseline of ≥100 points. CDAI is a scoring system for the assessment of Crohn's Disease Activity, index values of 150 and below are associated with quiescent disease; values above that indicate active disease and values above 450 are seen with extremely severe disease.
Part B: Percentage of Participants Achieving Clinical Response at Week 52	Baseline and Week 52	Clinical response is defined as CDAI decrease from Baseline of ≥100 points. CDAI is a scoring system for the assessment of Crohn's Disease Activity, index values of 150 and below are associated with quiescent disease; values above that indicate active disease and values above 450 are seen with extremely severe disease.
Part A: Percentage of Participants Achieving Clinical Remission at Week 10	Week 10	Clinical remission is defined as CDAI score of ≤150 points. CDAI is a scoring system for the assessment of Crohn's Disease Activity, index values of 150 and below are associated with quiescent disease; values above that indicate active disease and values above 450 are seen with extremely severe disease.
Part A: Percentage of Participants Achieving Clinical Remission at Week 26	Week 26	Clinical remission is defined as CDAI score of ≤150 points. CDAI is a scoring system for the assessment of Crohn's Disease Activity, index values of 150 and below are associated with quiescent disease; values above that indicate active disease and values above 450 are seen with extremely severe disease.
Part B: Percentage of Participants Achieving Clinical Remission at Week 52	Week 52	Clinical remission is defined as CDAI score of ≤150 points. CDAI is a scoring system for the assessment of Crohn's Disease Activity, index values of 150 and below are associated with quiescent disease; values above that indicate active disease and values above 450 are seen with extremely severe disease.
Part B: Percentage of Participants With Durable Clinical Remission	Weeks 26 and 52	Durable clinical remission is defined as clinical remission at both Week 26 and Week 52. Clinical remission is defined as CDAI score of ≤150 points. CDAI is a scoring system for the assessment of Crohn's Disease Activity, index values of 150 and below are associated with quiescent disease; values above that indicate active disease and values above 450 are seen with extremely severe disease. The percentage of participants assessed at Week 52 who had clinical remission at Week 26 of Part A and also had clinical remission at Week 52 is reported.
Part A: Percentage of Participants Achieving Clinical Response at Week 10	Baseline and Week 10	Clinical response is defined as Crohn's Disease Activity Index (CDAI) decrease from Baseline of ≥100 points. CDAI is a scoring system for the assessment of Crohn's Disease Activity, index values of 150 and below are associated with quiescent disease; values above that indicate active disease and values above 450 are seen with extremely severe disease.

Countries

Belgium, Canada, Czechia, France, Hungary, Italy, Poland, United States

Participant flow

Recruitment details

Participants took part in the study at 42 investigative sites in Belgium, Canada, Czech Republic, France, Hungary, Italy, Poland and the United States from 30 March 2015 to 21 February 2018.

Pre-assignment details

Participants with a diagnosis of Crohn's Disease were enrolled and received vedolizumab.

Participants by arm

Arm	Count
Vedolizumab 300 mg Part A: Vedolizumab 300 mg, intravenously (IV), once on Day 1 and Weeks 2, 6, 14 and 22, followed by Part B: Vedolizumab 300 mg, intravenously (IV), once at Weeks 30, 38, and 46.	101
Total	101

Withdrawals & dropouts

Period	Reason	FG000
Part A: Treatment Period	Lack of Efficacy	15
Part A: Treatment Period	Lost to Follow-up	2
Part A: Treatment Period	Pretreatment Event/Adverse Event	2
Part A: Treatment Period	Voluntary Withdrawal	4
Part B: Treatment Extension Period	Lack of Efficacy	7
Part B: Treatment Extension Period	Pretreatment Event/Adverse Event(s)	3

Baseline characteristics

Characteristic	Vedolizumab 300 mg
Age, Continuous	38.0 years STANDARD_DEVIATION 14
Body Mass Index (BMI)	24.71 kg/m^2 STANDARD_DEVIATION 5.365
Female Reproductive Status Female of Childbearing Potential	34 Participants
Female Reproductive Status N/A (Participant is a Male)	52 Participants
Female Reproductive Status Postmenopausal	6 Participants
Female Reproductive Status Surgically Sterile	9 Participants
Height	172.5 cm STANDARD_DEVIATION 9.81
Number of Participants with Endoscopic Remission	3 Participants
Race/Ethnicity, Customized Asian	2 Participants
Race/Ethnicity, Customized Black or African American	1 Participants
Race/Ethnicity, Customized Hispanic or Latino	1 Participants
Race/Ethnicity, Customized Non-Hispanic and Latino	32 Participants
Race/Ethnicity, Customized Not Collected	68 Participants
Race/Ethnicity, Customized White	98 Participants
Region of Enrollment Belgium	8 Participants
Region of Enrollment Canada	14 Participants
Region of Enrollment Czech Republic	14 Participants
Region of Enrollment France	2 Participants
Region of Enrollment Hungary	14 Participants
Region of Enrollment Italy	9 Participants
Region of Enrollment Poland	7 Participants
Region of Enrollment United States	33 Participants
Sex: Female, Male Female	49 Participants
Sex: Female, Male Male	52 Participants
Smoking Classification Participant has never smoked	46 Participants
Smoking Classification Participant is a current smoker	33 Participants
Smoking Classification Participant is an ex-smoker	22 Participants
Weight	73.94 kg STANDARD_DEVIATION 18.795

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 101	0 / 56
other Total, other adverse events	26 / 101	9 / 56
serious Total, serious adverse events	12 / 101	6 / 56

Outcome results

Primary

Part A: Percentage of Participants Achieving Endoscopic Remission at Week 26

Endoscopic remission is defined as a simple endoscopic score for Crohn's Disease (SES-CD) score of ≤4. The SES-CD evaluates 4 endoscopic variables (ulcer size, proportion of the surface area that is ulcerated, proportion of the surface area affected, and stenosis in 5 segments evaluated during ileocolonoscopy (ileum, right colon, transverse colon, left colon, and rectum). The score for each endoscopic variable is the sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 56, where higher scores indicate more severe disease.

Time frame: Week 26